In patients with chronic pain complicated by any number of comorbid conditions, a biopsychosocial approach is often necessary to treat the whole person. Understanding both related and unrelated comorbidities may also guide the clinician toward specific medications to use, or to eliminate, when treating the diagnoses. This article will explore how comorbidities play a role in the selection of non-opioid medications for pain management using the example of a patient with diabetic peripheral neuropathy and chronic kidney disease.

This case is the third in a four-part series exploring how comorbidities play a role in the selection of medications for pain management. Case 1 reviewed non-opioid options for a patient with chronic pain complicated by hypertension and post-traumatic stress disorder;1Case 2 focused on the use of buprenorphine in a patient with osteoarthritic pain, complicated by chronic obstructive pulmonary disease;2 and Case 4 focused on the use of opioids in those with chronic kidney disease and diabetic peripheral neuropathy.

The Patient

Mr. Stevens is a 68-year-old male with diabetic peripheral neuropathy. His past medication history is significant for Type 2 diabetes, uncontrolled hypertension, chronic kidney disease with CrCl = 43 mL/min, and benign prostatic hypertrophy (BPH). The patient has a history of alcohol use disorder that was in remission until recently. He reports that he has been drinking 10 beers a day lately for his pain but wants to return to sobriety.

The patient was started on amitriptyline 25 mg daily a week prior for pain control, and his wife is reporting that he has been confused and is having problems urinating. He presents to you for help with his pain.

Discussion of Options

While this article is focused on pharmacological approaches, non-pharmacological approaches, such as cognitive behavioral therapy, mindfulness, and relaxation, may also be considered and included in the care plan. For those with substance use disorders, referring them to appropriate providers for treatment is essential. Additionally, the patient should be educated on how alcohol may negatively impact his pain, as well as his physical and mental health.

TCAs

Tricyclic antidepressants (TCAs) are mainly FDA-labeled for the treatment of major depressive disorder.3-6 They are not indicated for treating chronic pain; however, numerous guidelines recommend TCAs off-label as a first-line treatment for neuropathic pain (see Table I).7-11 In addition, there is evidence for the use of TCAs in treating low back pain, fibromyalgia, and migraine prophylaxis.12 Their proposed mechanism of action is through inhibition of the descending pain pathway with effects independent of their antidepressant activity.12 Typically, TCAs are initiated at 10 to 25 mg daily at bedtime and titrated by 25 mg/day every 3 to 7 days up to a maximum of 150 mg/day. Although doses of more than 100 mg/day have been associated with sudden cardiac death,13,14 lower doses with a quicker onset of effect have been seen when TCAs are used to treat pain compared to depression.15

(Source: Author provided)

The use of TCAs is often limited by their adverse effects. Tolerability differs between tertiary amines (amitriptyline and imipramine), which are metabolized into secondary amines (nortriptyline and desipramine). Secondary amines have similar effectiveness to tertiary amines with enhanced tolerability.13 Another major issue to consider when prescribing TCAs are their anticholinergic adverse effects. Secondary amines interact less with antimuscarinic receptors, which contributes to their improved tolerability.16 Effects may include dry mouth, urinary retention, constipation, tachycardia, confusion, and blurred vision. The elderly are particularly susceptible to these effects and it is considered best practice to avoid using TCAs in this population.16

Another significant issue associated with TCAs are cardiovascular adverse effects. TCAs are related to Class Ia antiarrhythmics, which are known to inhibit voltage-gated sodium channels. Also, TCAs may inhibit alpha-adrenergic receptors and muscarinic-adrenergic receptors. A myriad of cardiac concerns, including slowed cardiac conduction, QTc prolongation, arrhythmias, tachycardia, and orthostatic hypotension, may occur with the use of TCAs.16 Due to the potential for worsening other conditions, TCAs should also be avoided in patients with glaucoma, cognitive impairment, or BPH.16 Further, because of interaction with histamine receptors, TCAs may lead to weight gain and sedation. The sedating effects may be more useful in a patient experiencing insomnia.16

In this case, the patient’s worsening urinary retention and confusion is likely at least partly attributed to his use of amitriptyline, although his alcohol intake may also be contributing to his memory issues. Based on the patient’s BPH and age, it would be advised that he avoid TCAs and discontinue the medication. A taper off of the medication is not needed due to the low dose.

SNRIs and Gabapentinoids

As it regards treating this patient’s neuropathy, serotonin norepinephrine reuptake inhibitors (SNRIs) are not a great option due to his elevated blood pressure. The patient’s consumption of large amounts of alcohol is a precaution (not contraindication) with the use of duloxetine.17 Gabapentinoids, however, offer another first-line treatment option for neuropathic pain.

Gabapentinoids, which include gabapentin and pregabalin, work by blocking the alpha-2-delta subunit of the voltage-gated calcium channel, leading to reduced levels of excitatory neurotransmitters.13,18 Gabapentin is FDA-indicated for post-herpetic neuralgia (PHN) and adjunctive treatment for partial onset seizures, but is often used off-label for treating neuropathic pain.18 Pregabalin has several pain-related indications including diabetic peripheral neuropathy, PHN, fibromyalgia, and neuropathic pain associated with spinal cord injury as well as adjunctive treatment of partial onset seizures in adults.19 Other uses of gabapentinoids may include restless legs syndrome, anxiety, and insomnia.13 Recent guidelines from the American Psychiatric Association for the pharmacological treatment of alcohol use disorder suggest the use of topiramate or gabapentin. (These medications may be offered to those who failed or have contraindications to naltrexone and acamprosate or prefer topiramate or gabapentin.) Therefore, gabapentin may be used to target the case patient’s neuropathic pain while also potentially helping to reduce his use of alcohol.20 (See more guidelines for neuropathic pain in Table I.)

Typically, gabapentin is initiated at 100 to 300 mg by mouth at bedtime or 100 to 300 mg three times daily. The dose may then be titrated in 100 to 300 mg/day increments every 3 to 7 days until effect, as tolerated, up to a maximum dose of 3600 mg/day.13 Importantly, gabapentin (and pregabalin) require renal dose adjustments beginning at CrCl < 60 mL/min.18 For Mr. Stevens, with a CrCl = 43mL/min, the recommended maximum dose would be 1,400 mg/day in two divided doses. The total daily dose should not only be reduced but the frequency of dosing should also change. Slow dosage titration will be essential to lessen adverse effects. Common side effects may include dizziness and sedation. Another typical adverse effect is peripheral edema.13,18 Infrequently, although with increasing reports, gabapentinoids have been associated with misuse and abuse (Note: PPM is polling its readers about this online; look for feedback reports in early 2019). Patients with a history of substance use disorder, particularly opioid use disorder, may be at higher risk for gabapentinoid abuse. Thus, it is important to monitor the patient’s adherence and look for signs of misuse and abuse.21 (Note: See also Part 1 in this case series for a table listing which medical conditions may benefit from TCAs, SNRIs, and gabapentinoids.1)

Conclusion

Patient-specific factors, including comorbidities, are important considerations when selecting non-opioid medications. These may help clinicians decide to use a medication to treat more than diagnosis concurrently. Also, a comorbidity may steer prescribers away from using a specific medication. In this particular case, the elderly patient presenting with painful diabetic peripheral neuropathy, BPH, and a likely alcohol use disorder may do best to discontinue any TCA usage that is worsening his BPH and leading to confusion and try a slow-dose titration of gabapentin to help manage his pain and possibly reduce his alcohol use.

Bril V, et al. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular Electrodiagnostic Medicine, American Academy of Physical Medicine and Rehabilitation. Neurol. 2011;76(20):1758-1765.

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